Abstract

The cytokine interferon gamma (IFN-γ) stimulates neopterin release and tryptophan degradation into kynurenines through the kynurenine pathway. High levels of neopterin were associated with increased hip fracture risk, as were some of the kynurenines, suggesting a role of IFN-γ-mediated inflammation in the processes leading to hip fracture.

INTRODUCTION:

Low-grade systemic inflammation has been associated with bone loss and risk of fractures. Interferon gamma (IFN-γ) initiates macrophage release of neopterin and also stimulates degradation of tryptophan along the kynurenine pathway as part of cell-mediated immune activation. Plasma neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-γ-mediated inflammation. Risk of hip fracture was investigated in relation to markers of inflammation and metabolites in the kynurenine pathway (kynurenines).

METHODS:

Participants (71 to 74 years, N = 3,311) in the community-based Hordaland Health Study (HUSK) were followed for hip fractures from enrolment (1998-2000) until 31 December 2009. Plasma C-reactive protein (CRP), neopterin, KTR, and six kynurenines were investigated as predictors of hip fracture, using Cox proportional hazards regression analyses.

RESULTS:

A hazard ratio (HR) of 1.9 (95% confidence interval (CI) 1.3-2.7) for hip fracture was found in the highest compared to the lowest quartile of neopterin (p trend across quartiles <0.001). CRP and KTR were not related to hip fracture risk. Among the kynurenines, a higher risk of fracture was found in the highest compared to the lowest quartiles of anthranilic acid and 3-hydroxykynurenine. For subjects in the highest quartiles of neopterin, CRP, and KTR compared to those in no top quartiles, HR was 2.5 (95% CI 1.6-4.0).

CONCLUSIONS:

This may indicate a role for low-grade immune activation in the pathogenic processes leading to hip fracture.

The kynurenine pathway of tryptophan metabolism. Degradation of the essential amino acid tryptophan through the kynurenine pathway is initiated by either indoleamine 2,3-dioxygenase or by tryptophan dioxygenase (TDO). TDO is primarily found in the liver and is induced by tryptophan and corticosteroids, whereas IDO is an ubiquitous enzyme induced by cytokines. AMO anthranilate monooxygenase, KAT kynurenine aminotransferase, KMO kynurenine monooxygenase, KYNU kynureninase

Kaplan-Meier survival curves for time to hip fracture in 3,178 men and women (71–74 years at inclusion), stratified on subjects in the highest quartiles of none (n = 1,638), one (n = 879), two (n = 490), or three (n = 171) inflammation markers (CRP, neopterin, kynurenine/tryptophan ratio). The Hordaland Health study

Venn diagram showing the distribution of participants in the Hordaland Health Study according to inflammatory status assessed as any combination of inflammatory markers in the upper quartile of each marker. Of the 3,178 participants with measurements of all three inflammatory markers, 1,638 (51.5 %) persons were not in the highest quartile of any of the inflammatory markers. The correct proportional overlap between the inflammatory markers is shown, and numbers show percentages of the total cohort